Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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CA16020963

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e332e684-4317-4e4f-981a-fe45ddb7355c

HGVS expressions

NM_001354304.2:c.1199+50G>A

ENST00000553106.6:c.1199+50G>A

ENST00000307000.7:c.1184+50G>A

ENST00000549247.6:n.958+50G>A

ENST00000551114.2:n.861+50G>A

ENST00000553106.5:c.1199+50G>A

ENST00000635477.1:n.303+50G>A

ENST00000635528.1:n.714+50G>A

NM_000277.1:c.1199+50G>A

NM_000277.2:c.1199+50G>A

NM_001354304.1:c.1199+50G>A

NM_000277.3:c.1199+50G>A

NC_000012.12:g.102843596C>T

CM000674.2:g.102843596C>T

NC_000012.11:g.103237374C>T

CM000674.1:g.103237374C>T

NC_000012.10:g.101761504C>T

NG_008690.1:g.79007G>A

NG_008690.2:g.119815G>A

Uncertain Significance

BP7 PM2

BP2 PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1199+50G>A intronic variant has been reported homozygous in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels with BH4 deficiency excluded. However, this patient is also homozygous for c.441+1G>C (ClinVar 556894, Pathogenic). The c.1199+50G>A variant is present a low frequency in gnomAD with a MAF of 0.000008870 in the South Asian population but it is not highly conserved and is not predicted to have a deleterious effect. Splicing predictors are in consensus that there is no significant impact on splicing signals. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, BP7.

BP7

HSF, MaxEntScan, and SpliceAI agree that there is no significant impact on splicing signals and the nucleotide is not highly conserved (PhyloP score of -0.196315).

PM2

This variant is at an extremely low frequency (below the <1/5,000 threshold) with an overall allele frequency from gnomAD of 0.000003993 and MAF of 0.000008870 (1/30518 alleles) in the South Asian population.

BP2

Patient 14 of PMID: 24048906 is homozygous for this c.1199+50G>A as well as c.441+1G>C (ClinVar 556894 Pathogenic, reviewed by VCEP). This criteria is considered not applicable by the expert panel.

PP4

Reported in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis. The patient is homozygous for this c.1199+50G>A as well as c.441+1G>C (ClinVar 556894 Pathogenic, reviewed by VCEP), PP4 is not applied here as this patient's phenotype was considered in the curation of c.441+1G>C.

Approved on: 2020-09-04

Published on: 2021-07-25

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